p53 is one of the most important tumor suppressor genes. In approximately half of all human cancers, p53 is inactivated as a direct result of mutations in the p53 gene (Hollstein et al., Science 1991; 253:49-53, Levine et al., Nature 1991; 351:453-6). In other cancers, p53 is inactivated through its association with viral oncoproteins, or as a result of alterations in genes that are involved in the p53 signaling network (Vogelstein et al., Nature 2000; 408:307-10). Furthermore, mutation or deletion of p53 is related to poor prognosis and resistance to chemotherapy and radiation (Clarke et al., Oncogene 1994; 9:1767-73, Merritt et al., Cancer Res 1994; 54:614-7, Poeta et al., N Engl J Med 2007; 357:2552-61, Patocs et al., N Engl J Med 2007; 357:2543-51).
Vector-mediated gene transfer of p53 is viewed as a potentially effective cancer therapy. In fact, clinical trials of adenovirus-mediated p53 gene therapy are ongoing in patients with head and neck (Phase III), non-small cell lung (Phase II), breast (Phase II) and esophageal (Phase II) cancer (INGN 201: Ad-p53, Ad5CMV-p53, adenoviral p53, p53 gene therapy-introgen, RPR/INGN 201. Drugs R D 2007; 8:176-87). However, gene transfer of p53 does not always have a good therapeutic outcome for all cancers (Roth et al., Nat Med 1996; 2:985-91, Swisher et al., J Natl Cancer Inst 1999; 91:763-71, Nemunaitis et al., J Clin Oncol 2000; 18:609-22). Thus, further refinement in p53-directed gene therapy is required.
The activation of p53 is induced by a variety of cell stresses, such as DNA damage, oncogene activation, spindle damage and hypoxia. Activated p53 transactivates a number of genes, many of which are involved in DNA repair, cell cycle arrest and apoptosis (Riley et al., Nat Rev Mol Cell Biol 2008; 9:402-12). Depending on the cell type and intensity of stress, p53 activation induces either cell cycle arrest or apoptosis (Zhang et al., Environ Health Perspect 2007; 115:653-8). However, the precise mechanism that regulates whether a cell undergoes cell cycle arrest or apoptosis is still unclear.